title: Anti-stromal therapy with imatinib inhibits growth and metastasis of gastric carcinoma in an orthotopic nude mouse model.
abstract: Recent studies have revealed that platelet-derived growth factor (PDGF) plays a role in promoting progressive tumor growth in several organs; however, whether PDGF plays such a role in gastric carcinoma is undetermined. We examined whether inhibition of PDGF receptor (PDGF-R) tyrosine kinase signaling by imatinib affects tumor growth and metastasis in an orthotopic nude mouse model of human gastric carcinoma. TMK-1 human gastric carcinoma cells were injected into the gastric wall of nude mice. Groups of mice (n = 10 each) received sterile water (control), low-dose imatinib (50 mg/kg/day), high-dose imatinib (200 mg/kg/day), cancer chemotherapeutic agent irinotecan (5 mg/kg/week), or imatinib (50 mg/kg/day or 200 mg/kg/day) and irinotecan (5 mg/kg/week) in combination for 28 days. Tumor growth and metastasis were assessed. Resected tumors were analyzed immunohistochemically. Carcinoma-associated fibroblasts, pericytes and lymphatic endothelial cells in stroma expressed high levels of PDGF-R; carcinoma cells did not. Treatment with imatinib alone did not inhibit tumor growth and metastasis; however, treatment with irinotecan alone or combined with imatinib significantly inhibited tumor growth. Only treatment with high-dose imatinib and irinotecan in combination inhibited lymph node and peritoneal metastases. Immunohistochemically, only imatinib alone or in combination with irinotecan was shown to significantly decrease the stromal reaction, microvessel area and pericyte coverage of tumor microvessels. These effects were marked with high-dose imatinib. In conclusion, administration of PDGF-R tyrosine kinase inhibitor in combination with irinotecan appears to impair the progressive growth of gastric carcinoma by blockade of PDGF-R signaling pathways in stromal cells.
authors.affiliation: Department of Medicine and Molecular Science, Graduate School of Biomedical Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Sumida
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kitadai
authors.forename: Kei
authors.initials: K
authors.lastname: Shinagawa
authors.forename: Miwako
authors.initials: M
authors.lastname: Tanaka
authors.forename: Michiyo
authors.initials: M
authors.lastname: Kodama
authors.forename: Mayu
authors.initials: M
authors.lastname: Ohnishi
authors.forename: Eiji
authors.initials: E
authors.lastname: Ohara
authors.forename: Shinji
authors.initials: S
authors.lastname: Tanaka
authors.forename: Wataru
authors.initials: W
authors.lastname: Yasui
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001549:Benzamides; D015153:Blotting, Western; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D000077146:Irinotecan; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009362:Neoplasm Metastasis / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010879:Piperazines / Q000008:administration & dosage / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000077146:Irinotecan; D000068877:Imatinib Mesylate; D017479:Receptors, Platelet-Derived Growth Factor; D002166:Camptothecin